Lung Cancer is the leading cause of cancer death in women and men in the U.S. It is estimated that there will be more than 230,000 patients diagnosed with lung cancer this year, with more than 160,000 deaths, and non-small cell lung cancer (NSCLC) will account for more than three quarters of these cases (1). Survival rates of NSCLC, the predominant type of lung cancer are unacceptably low, and new approaches to treat and prevent this disease are urgently needed. Feverfew extracts and parthenolide show anticancer activity in NSCLC in vitro, while parthenolides modified to enhance solubility also show significant anticancer activity in vivo in NSCLC models. This anticancer effect may be associated with the ability of these substances to inhibit the nuclear transcription factor kappaB (NFκB) possibly leading in turn to the promotion of tumor cell apoptosis (3). Disclosed herein is a study of the role of feverfew extract and parthenolide in the treatment and prevention of NSCLC.
At diagnosis, about 70% of breast cancer patients have tumors that express estrogen receptors (ER) and/or progesterone receptors (PR). Patients with ER+ tumors can be treated with hormonal therapy such as tamoxifen which was the first effective targeted therapy for breast cancer. However, all advanced ER+ tumors eventually develop endocrine resistance, and there is an urgent need for new interventions to stop endocrine resistance. Mechanisms of endocrine resistance include HER2 overexpression (occurs in 15-20% of patients) and increased activation of NFκB signaling pathways. Activation of tumor NFκB occurs in ER+ breast cancers with resistance to hormonal therapy and in HER2+ breast tumors with resistance to Trastuzumab (Herceptin). Parthenolide analogues that block activation of NFκB are active in restoring breast tumor responses to hormonal and Trastuzumab therapies, thereby potentially helping to improve patient outcomes
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with development of hamartomatous lesions in many organs (71-74). Some lesions grow progressively and require clinical intervention. TSC is due to mutations in either TSC1 or TSC2 genes. TSC1 (hamartin)/TSC2 (tuberin) protein complexes serve a critical role in negatively regulating mTOR complex 1 (mTORC1) which exerts downstream effects on cell transcription, translation, metabolism and proliferation. mTORC1 is constitutively active in cells lacking either TSC1 or TSC2 and in hamartomas of TSC patients. TSC can occur in association with pulmonary lymphangioleiomyomatosis (LAM), a progressive and often fatal interstitial lung disease that occurs largely in women and is characterized by proliferation of abnormal smooth muscle cells. TSC2-null smooth muscle cells in angiomyolipomas (AML) are very similar to those of pulmonary LAM, and data suggest LAM may be the result of benign cell metastases. Rapamycin and related drugs (everolimus) which bind and inhibit mTORC1 have clinical activity for therapy of TSC, including renal AML and pulmonary LAM (72). However, rapamycin does not elicit complete TSC regression in most cases, and termination of therapy oft leads to lesion re-growth. New therapeutic approaches to control the growth of TSC-related proliferative diseases are urgently needed.
The poor prognosis of advanced non-small cell lung cancer (NSCLC) is due, in part, to emergence of tumor resistance to chemotherapy (1). Recent data indicate that human tumors contain a small subset of cancer stem cells (CSC) responsible for drug resistance and tumor maintenance (2-5). If such minute subsets of CSC drive tumor formation and drug resistance, therapies targeting the bulk tumor mass but not CSC will fail. Since it is hypothesized that CSC are responsible for tumor regeneration after chemo-therapy (6), we performed preliminary studies to determine if drug treatment could enrich for CSCs. Treatment of human lung tumor NSCLC cell lines (A549, H23) with increasing doses of cisplatin resulted in selection of drug-resistant cells (DRC)(6). Using Fluorescence Activated Cell Sorting (FACS), DRC were selected for expression of cell surface CD133+ and cytosolic ALDH1 by Aldefluor assay (7,8), yielding cell subsets amounting to 2%-5% of bulk tumor cell populations of H23 and A549, respectively. Furthermore, CSC-like cells grew as tumor spheres, maintained self-renewal capacity and differentiated, with differentiated progenitors losing CD133 expression and acquiring drug sensitivity. These initial studies suggest that chemotherapy leads to propagation of CSC. Importantly, resistance of CSC-like cells to cisplatin was fully reversed by treatment with parthenolide (PTL). The antitumor effect of PTL has been reported to selectively kill CSCs through inhibition of nuclear factor-κB (NF-κB) which is markedly activated by chemotherapy (9).
The aromatic plant known as feverfew (Tanacetum parthenium) has been used in folk medicine to treat a number of different human maladies. The plant is notably rich in a family of compounds known as sesquiterpene lactones, particularly parthenolide. One of the most important characteristics of parthenolide is its antitumor activity, with reports of cytotoxic activity against epidermoid carcinoma, fibrosarcoma, hepatocellular carcinoma, breast and prostate cancer, and leukemia and lymphoma cells. This compound has been demonstrated in vitro to inhibit different type of cancer cells (2,4,5). Parthenolide may promote apoptosis in neoplastic cells in part by inhibiting the cancer-promoting factor, NFκB, a critical regulator of genes involved in tumor cell proliferation, antiapoptosis (anti-cell death), DNA damage responses and angiogenesis (2,4,6,7). Inhibition of NFκB signaling leads to reduced expression of many proteins including antiapoptotic proteins. The downstream consequences of these effects lead to cell cycle arrest and cell death (2,8). Unfortunately, both feverfew herbal extract and native parthenolide have limited in vivo activity due to poor bioavailability (9). Hence, the inventors have developed improved derivatives of these naturally-occurring compounds to be used as drug-like agents to treat and prevent lung cancer and other human malignancies.
Breast cancer is a worldwide health concern with about 1,000,000 million new cases each year. In the clinic, endocrine therapy is an important intervention in women with breast cancers that express estrogen receptor (ER), and treatment with tamoxifen has enhanced patient survival. The success of endocrine therapy is dependent on tight regulation of breast cell growth by steroids and growth factor receptors (27) most patients eventually stop responding to antiestrogen therapy. Resistance to tamoxifen (TAM) and aromatase inhibitors represents a major drawback to treatment of hormone-dependent breast cancer, and new options for endocrine therapy are urgently needed to reverse this outcome. Emerging data now confirm the existence of previously-unsuspected interactions between growth factor and estrogen signaling pathways that contribute to growth regulation in breast cancers. Targeting this signaling axis may promote introduction of more effective and less toxic antihormone treatments for human breast cancers (28-30).
Subversion of growth factor receptors often occurs in malignancy, and members of the HER family are often implicated in cancer (31). EGF receptor (EGFR), a 170-kD transmembrane protein, has an extracellular ligand-binding domain, a membrane-spanning region and a cytoplasmic EGF-stimulated tyrosine kinase. On EGF binding, EGFR undergoes dimerization and autophosphorylation on tyrosine residues. This results in activation of downstream protein kinases, such as MAP kinase and PI3 kinase/Akt kinase, and subsequent stimulation of transcription factors. The HER family includes other receptor tyrosine kinases including HER-2, a 185-kD kinase encoded by HER-2/neu oncogene, as well as HER-3 and HER-4. HER-2 receptor functions similar to EGFR (30-33), and, on binding of ligand to EGF, HER-3 or HER-4, HER-2 is often recruited as a preferred partner to form heterodimers that activate downstream signaling for growth and survival. Overexpression of HER-2 or related HER receptors occurs in two-thirds of sporadic breast tumors, while HER-2 over-expression/amplification is found in 25-30% of breast cancers (32,33). Overexpression of HER-2 is generally a marker of poor prognosis (7), and it associates with failure of antiestrogen therapy in the clinic (28,34-38).
It is generally held that biologic activity of estrogen in breast cells is mediated by its binding with high-affinity ER in the nucleus (27,39) (see FIG. 10).
Upon estrogen binding, ER undergoes an activating conformational change that allows association with coactivators and target genes, thus promoting regulation of gene transcription. Ligand-bound ER in the nucleus functions as a transcription factor. Blocking estrogen binding to ER is the basis of the action of tamoxifen, a partial agonist that limits proliferative effects of estrogen in breast, while fulvestrant (Faslodex) is a new generation antiestrogen with a mechanism of action leading to downregulation of ER in tumors (42,43). In addition to nuclear actions of estrogens, numerous reports document rapid effects of estradiol mediated by a membrane-associated ER that derives from the same transcript as nuclear ER (34-46) (FIG. 10). Interactions between ER and growth factor receptors occur in lipid rafts, assemblies of cholesterol and sphingolipids in plasma membrane (47). Caveolae are specialized rafts present in most cells (48,49), but they are markedly reduced or absent in breast cancer cells (50). Caveolae and lipid rafts are enriched in growth factor receptors, including HER-2 receptors (48), and a portion of ER also localize in caveolae and lipid rafts (51,52).
Conversion of estrogen-sensitive to -resistant tumors after the start of antiestrogen therapy is a major problem in the clinic (65). This resistance may be due, in part, to enhanced growth factor signaling, a cellular response to antiestrogen treatment that eventually results in increased phosphorylation of ER and/or coactivators, such as AIB1(54). Convergence between growth factor and estrogen signaling may elicit a synergistic feed-forward circuit with more robust cell growth (FIG. 10). It is notable that tumors with HER-2 overexpression tend to respond poorly to antiestrogens (69-72). A meta-analysis of 7 clinical trials indicated that breast tumors with HER-2 overexpression were resistant to tamoxifen (73-75). Such clinical data offer further evidence of the biologic interaction between HER-2 and ER. To evaluate the relation of HER-2 to clinical antiestrogen resistance, we used estrogen-responsive, MCF-7 cells with defined levels of ER that were transfected with HER-2 gene (MCF-7/HER-2). MCF-7 cells+HER-2 overexpression and parent MCF-7 cells were grown as xenografts in nude mice as before (28) (FIGS. 11A-11B). As expected, growth of parent cells was markedly suppressed by tamoxifen and by fulvestrant (FIGS. 11A-11B). In contrast, MCF-7/HER-2 cells were insensitive to tamoxifen, but retained partial sensitivity to fulvestrant (28). This correlates with data from the clinic suggesting tamoxifen resistance in breast tumors with high levels of HER-2 expression.
Two important systems that transmit extracellular signals into the machinery of the cell nucleus are the signaling pathways that activate nuclear factor κB (NF-κB) and estrogen receptor (ER). These two transcription factors induce expression of genes that control cell fates, including proliferation and cell death (apoptosis). Estrogen receptor (ER) and nuclear factor-kappaB (NFκB), a major regulator of pathways central to malignant progression, are known to be mutually inhibitory at several molecular levels. It has been suggested that in some ER-positive breast cancers SERMS such as tamoxifen can activate NFκB, stimulate cell growth and survival, and thereby contribute to endocrine resistance (62). Recent investigations elucidated a previously unsuspected effect of ER, namely inhibition of NFκB activation. In breast cancer, antiestrogen therapy might cause reactivation of NFκB, potentially re-routing a proliferative signal to breast cancer cells and contributing to hormone resistance (63). Thus, ligands that selectively block NFκB activation, such as parthenolides, could provide specific potential therapy for hormone-resistant ER-positive breast cancers (see FIG. 12). Disclosed herein, inter alia, are solutions to these and other problems in the art.